A variety of measures has conventionally been practised with respect to sustained release drug preparations, namely, with respect to such drug preparations containing a medical compound and capable of retarding or prolonging the release of the medical compound from the drug preparation to maintain the efficacy of the medical compound in vivo for a long time. For example, there have been practised such method where crystals, granules or tablets comprising medical compound are coated with a hydrophobic substance such as wax or the like; such method where a large amount of a binder and/or a hydrophobic lubricant is or are mixed with medical compound; and such method where a medical substance is wrapped with a semipermeable membrane. On the other hand, it is known that inclusion complex may be obtained by complexing a guest compound or molecule with cyclodextrin as a host compound or molecule. And, such inclusion complexes with cyclodextrin have been used almost for the purpose of enhancing the stability of a guest compound against heat or light or in air (Japanese Patent Application first publication "Kokai" No. 154479/81), for the purpose of masking a bitter taste or unpleasant odor of a guest compound (Japanese Patent Application first publication "Kokai" No. 137867/81), for the purpose of solubilizing a hardly soluble substance (Japanese Patent Application first publication "Kokai" No. 48849/81), for the purpose of utilizing as emulsion stabilizers (Japanese Patent Application first publication "Kokai" No. 21552/81), or for the purpose of improving absorption rate of a guest compound in vivo. But, no attempt has heretofore been made that such an inclusion complex, which is obtained by complexing a guest compound with cyclodextrin as a host compound, is used with a view to achieving sustained release of or prolonged maintenance of the medical efficacy of a medical compound.
We, the present inventors, have carried out extensive investigations on the possibility that such inclusion complexes, which are formed by complexing cyclodextrin or cyclodextrin derivative as a host compound with a guest compound which is a medical compound capable of acting as an active ingredient in a drug, would be used as a drug or in the form of a sustained release drug preparation. As a result, we have now found that when medical compound is used as the guest compound and complexed with a hydrophobic alkylated cyclodextrin derivative as a host compound for formation of their inclusion complexes, such hydrophobic alkylated cyclodextrin derivatives, for example, ethylated cyclodextrin derivatives can have significant effects for the retardation of release of medical compound from said inclusion complexes, whereas hydrophilic .alpha.-, .beta.-and .gamma.-cyclodextrins and the other, hydrophilic cyclodextrin derivatives such as methylated cyclodextrin, hydroxypropylated cyclodextrin and branched cyclodextrin, which have conventionally been used as the host compound of the known inclusion complexes, do not have any substantial sustaining effects on the release of medical compound. Thus, we have found that formation of an inclusion complex by complexing a medical compound with a hydrophobic alkylated cyclodextrin can achieve so-called "molecular level" encapsulation of the medical compound, and hence that it is possible to develop such a sustained release inclusion complex and also such a sustained release drug preparation comprising said inclusion complex, which permit sustained and gradual release of the medical compound in vivo. On the basis of these findings, we have accomplished this invention. Incidentally, parts of the above finding were reported by the present inventors and certain associates at page 18 of a literature "Ko-en Yo-shi Shu of Fifth Cyclodextrin Symposium" published on 5 Dec. 1986 in Kyoto, Japan.
The previous procedures for retardation of release of a medical compound by coating or encapsulating the medical compound with some materials in an attempt to provide a sustained release drug preparation were tried but were not always satisfactory because of the difficulties involved in the selection of a coating agent or encapsulating material, the complexity of the coating or encapsulation procedures and the difficulties in the control of reproducibility of release retarding effects. In these circumstances, we, the present inventors, already tried to prepare and utilize such an inclusion complex where a hydrophilic cyclodextrin derivative was used as a host compound, and we conducted some research accordingly. Our previous research, however, failed to develop any drug preparation having significant release retarding effects.
Thereafter, in an attempt to provide the sustained release drug preparations, we have continued our researches with using as the host compounds such various cyclodextrin derivatives which are either hydrophobic or poorly soluble in water and which can form an inclusion complex with medical compound. As a result, we have now found that a hydrophobic alkylated cyclodextrin derivative, for example, ethylated cyclodextrins is suitable as the host compound to be complexed with a medical compound for formation of their inclusion complex, and is suitable for the production of sustained release drug preparations.
We have further found that, with an inclusion complex of a medical compound with a hydrophobic cyclodextrin derivative, the inherent medical activities of the medical compound can be maintained in vivo for a prolonged duration without modifying its inherent effectiveness. Moreover, the drug preparation comprising the above inclusion complex may take any dosage form. We have also found that the drug preparation comprising the inclusion complex according to the present invention may be either in the form of liquid preparation forms, such as injections and suspensions, or in the form of solid preparation forms such as tablets, powder, granules and capsules. According to the present invention, the designing of a drug preparation and maintenance of its quality can also be facilitated, since the sustained release of a medical compound from said complex is retained independently of pH. It is also expected that an inclusion complex of medical compound with a hydrophobic cyclodextrin derivative involks some changes in the physiochemical properties of the medical compound, whereby the stability of the medical compound against light and/or heat may be improved.
Thus, we, the present inventors, have found that when a medical compound has been complexed with a hydrophobic cyclodextrin derivative, for example, ethylated cyclodextrins to form their inclusion complex, the release of the medical compound from said complex can be controlled to less than the rate of dissolution and release of the medical compound itself. Furthermore, we have found that the hydrophobic ethylated cyclodextrin derivatives available according to this invention include the three particular compounds, namely heptakis(2,3-di-O-ethyl)-.beta.-cyclodextrin; heptakis(2,6-di-O-ethyl)-.beta.-cyclodextrin; and heptakis(2,3,6-tri-O-ethyl)-.beta.-cyclodextrin, and that these three particular ethylated .beta.-cyclodextrin derivatives can show different effects of sustaining the release of the medical compound from the inclusion complex. Thus, the release of a medical compound from the inclusion complex may be adjusted to a desired extent by selecting well these three particular ethylated .beta.-cyclodextrin derivatives suitably in combination for use in the formation of the inclusion complexes.